Method for producing perampanel derivatives including a continuous flow process

Abstract

The present application relates to a method for preparing perampanel derivatives comprising a continuous flow process.

Description

[Technical field]

[0001] The present application relates to a method for preparing perampanel derivatives comprising a continuous flow process. [Background technology]

[0002] Epilepsy is a disease in which brain cells undergo temporary abnormalities, becoming overexcited and temporarily paralyzing brain function, with symptoms including loss of consciousness, behavioral changes, and repeated seizures affecting parts of the body or the whole body. Epilepsy can be caused by impact to the head, as in a traffic accident, but the causes of epilepsy are extremely diverse and can occur without a clear cause. As seizures occur along nerves, the main purpose of drug treatment for epilepsy is to block nerve transmission and suppress convulsions.

[0003] Perampanel is an over-the-counter anti-epileptic drug, an AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor antagonist that suppresses neuronal hyperexcitation. Perampanel has high selectivity for AMPA receptors, and can reduce other side effects by irreversibly inhibiting only AMPA receptors, not NMDA (N-methyl-D-aspartate) receptors, and can effectively inhibit AMPA receptors by inhibiting them non-competitively, rather than competitively with glutamate.

[0004] Conventional methods for synthesizing perampanel use a batch process, which involves six or more batch steps, which is not only inefficient due to the large number of process steps, but also has problems such as reduced selectivity during the production of intermediate products. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Korean Patent Publication No. 10-2022-0029525 Summary of the Invention [Problem to be solved by the invention]

[0006] The present application aims to provide a method for producing perampanel derivatives, which comprises a continuous flow process.

[0007] However, the problems to be solved by the present application are not limited to those mentioned above, and other problems not mentioned will be clearly understood by those of ordinary skill in the art from the following description. [Means for solving the problem]

[0008] The first aspect of the present application is to (a) obtain a compound represented by the following formula 2 by protecting a compound represented by the following formula 1 with a tosyl group; (b) obtain a compound represented by the following formula 2 and R 1 -Li is supplied to a first microtube reactor and reacted to obtain a first intermediate product, and the first intermediate product and ZnCl 2 is supplied to a second microtube reactor and reacted to obtain a second intermediate product, and the second intermediate product and R 2 -X 2 (c) subjecting the compound represented by the following chemical formula 3 to a Stille reaction with 2-(tributylstannyl)pyridine to obtain a compound represented by the following chemical formula 4; and (d) subjecting the compound represented by the following chemical formula 4 to a tosyl group removal reaction and a Chan-Lam reaction to obtain a perampanel derivative represented by the following chemical formula 5. [ka] [ka] [ka] [ka] [ka] The Chemical Formulas 1 to 5, R 1 -Li, and R 2 -X 2 In R 1 is a linear or branched C 1-8 is an alkyl group, R 2 teeth, [ka] and R 2 The wavy line in the substituent represented by the formula: represents a linking site, X 1 and X 2 are each independently Br or I.

[0009] A second aspect of the present application provides a perampanel derivative produced by the method according to the first aspect.

[0010] A third aspect of the present application is a compound represented by the following formula 2 and R 1 (II) supplying ZnCl2 to a first microtube reactor and reacting the ZnCl2 to obtain a first intermediate product; and (II) reacting the ZnCl2 with the first intermediate product. 2 into a second microtube reactor and react to obtain a second intermediate product; and (III) reacting the second intermediate product and R 2 -X 2 by Negishi reaction to obtain a compound represented by the following chemical formula 3: [ka] [ka] The above-mentioned Chemical Formula 2, Chemical Formula 3, and R 1 -Li, and R 2 -X 2 In R 1 is a linear or branched C 1-8 is an alkyl group, R 2 teeth, [ka] and R 2 The wavy line of the substituent represented by the formula: 1 and X 2 are each independently Br or I. Effect of the Invention

[0011] The method for producing a perampanel derivative according to an embodiment of the present application uses a continuous flow process, which reduces the number of process steps compared to conventional methods for producing perampanel derivatives and improves selectivity when producing an intermediate product.

[0012] The method for producing a perampanel derivative according to an embodiment of the present disclosure can produce a perampanel derivative in high yield. [Brief description of the drawings]

[0013] [Figure 1] In one embodiment of the present application, a synthetic procedure for perampanel is provided. [Diagram 2] 1 is a reaction scheme showing a process for producing compound b from compound a in one embodiment of the present application. [Diagram 3]1 is a reaction scheme showing the preparation and continuous flow process of compound c from compound b in one embodiment of the present application. [Figure 4] 1 is a 1H-NMR spectrum of a derivative of compound c synthesized using 1-iodo-4-methylbenzene or 1-bromo-4-methylbenzene in one embodiment of the present application. [Diagram 5] 1 is a 1H-NMR spectrum of a derivative of compound c synthesized using 1-iodo-4-methoxybenzene or 1-bromo-4-methoxybenzene in one embodiment of the present application. [Figure 6] 1 is a 1H-NMR spectrum of a derivative of compound c synthesized using 1-iodo-4-trifluoromethylbenzene or 1-bromo-4-trifluoromethylbenzene in one embodiment of the present application. [Figure 7] 1 is a 1H-NMR spectrum of a derivative of compound c synthesized using methyl 4-iodobenzoate or methyl 4-bromobenzoate in one embodiment of the present application. [Figure 8] 1 shows 1H-NMR spectra of derivatives of compound c synthesized using 1-iodo-4-nitrobenzene or 1-bromo-4-nitrobenzene in one embodiment of the present application. [Figure 9] 1 is a 1H-NMR spectrum of a derivative of compound c synthesized using 2-iodopyridine or 2-bromopyridine in one embodiment of the present application. [Figure 10] 1 is a 1H-NMR spectrum of a derivative of compound c synthesized using 2-iodothiophene or 2-bromothiophene in one embodiment of the present application. [Figure 11] 1 is a reaction scheme showing a process for producing compound d from compound c in one embodiment of the present application. [Figure 12] 1 is a reaction scheme showing a process for producing perampanel from compound d in one embodiment of the present application. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] Hereinafter, the present application will be described in detail with reference to the accompanying drawings so that those skilled in the art can easily carry out the present application. However, the present application may be embodied in various different forms and is not limited to the embodiments and examples described herein. In the drawings, in order to clearly explain the present invention, parts that are not related to the description are omitted, and similar parts are designated by similar reference numerals throughout the specification.

[0015] Throughout the specification of this application, when a part is said to be "connected" to another part, this includes not only "directly connected" but also "electrically connected" with another element therebetween.

[0016] Throughout this specification, when a member is said to be "on" another member, this includes not only when the member is in contact with the other member, but also when there is another member between the two members.

[0017] Throughout the specification of this application, when a part is said to "comprise" a certain element, this means that it may further include other elements, but not to the exclusion of other elements, unless specifically stated to the contrary.

[0018] As used herein, terms of degree such as "about," "substantially," and the like are used to mean a numerical value or close to a numerical value when the manufacturing and material tolerances inherent in the recited value are given, and are used to prevent unscrupulous infringers from unfairly taking advantage of the disclosure in which precise or absolute numerical values ​​are recited to aid in the understanding of the present application.

[0019] As used throughout the specification of this application, the terms "a step of" or "a step of" do not mean "a step for."

[0020] Throughout the specification of this application, the term "combinations thereof" contained in a Markush form phrase means a mixture or combination of one or more selected from the group of elements set forth in the Markush form phrase, and is meant to include one or more selected from the group of elements.

[0021] Throughout the specification of this application, the statement "A and / or B" means "A or B, or A and B."

[0022] Hereinafter, specific examples of the present application will be described in detail, but the present application is not limited thereto.

[0023] The first aspect of the present application is to (a) obtain a compound represented by the following formula 2 by protecting a compound represented by the following formula 1 with a tosyl (Ts) group; (b) obtain a compound represented by the following formula 2 and R 1 -Li is supplied to a first microtube reactor and reacted to obtain a first intermediate product, and the first intermediate product and ZnCl 2 is supplied to a second microtube reactor and reacted to obtain a second intermediate product, and the second intermediate product and R 2 -X 2 (c) subjecting the compound represented by the following chemical formula 3 to a Negishi reaction to obtain a compound represented by the following chemical formula 3 and 2-(tributylstannyl)pyridine to a Stille reaction to obtain a compound represented by the following chemical formula 4; and (d) subjecting the compound represented by the following chemical formula 4 to a tosyl group removal reaction and a Chan-Ramu reaction to obtain a perampanel derivative represented by the following chemical formula 5. [ka] [ka] [ka] [ka] [ka] The Chemical Formulas 1 to 5, R 1 -Li, and R 2 -X 2 In R 1 is a linear or branched C 1-8 is an alkyl group, R 2 teeth, [ka] and R 2 The wavy line in the substituent represented by the formula: represents a linking site, X 1 and X 2 are each independently Br or I.

[0024] In one embodiment of the present application, the (a) may be a reaction of the compound represented by Formula 1 with a compound containing a tosyl group in the presence of a catalyst and an organic solvent. In one embodiment of the present application, the compound containing a tosyl group may include, but is not limited to, tosyl chloride. In one embodiment of the present application, for example, in the (a), about 1 equivalent of the compound represented by Formula 1, about 5 mol % of 4-dimethylaminopyridine (DMAP), about 5 mol % of triethylamine (Et 3 The compound represented by the formula 2 may be obtained by reacting about 2 equivalents of N) with about 2 equivalents of tosyl chloride (TsCl) at about 0° C. for about 12 hours.

[0025] In an embodiment of the present application, the yield of the compound represented by Formula 2 may be about 90% or more, or about 95% or more.

[0026] In one embodiment of the present application, the R 1 -Li may include, but is not limited to, one or more selected from methyllithium, ethyllithium, n-propyllithium, iso-propyllithium, n-butyllithium, sec-butyllithium, t-butyllithium, n-pentyllithium, iso-pentyllithium, sec-pentyllithium, neo-pentyllithium, 3-pentyllithium, sec-isopentyllithium, n-hexyllithium, iso-hexyllithium, sec-hexyllithium, 3-methylpentyllithium, sec-hexyllithium, heptyllithium, 2-ethylhexyllithium, n-octyllithium, and isomers thereof.

[0027] In one embodiment of the present application, the R 2 -X 2 may include, but is not limited to, one or more selected from 2-iodobenzonitrile, 1-iodo-4-methylbenzene, 1-iodo-4-methoxybenzene, 1-iodo-4-trifluoromethylbenzene, methyl-4-iodobenzoic acid, 1-iodo-4-nitrobenzene, 2-iodopyridine, 2-iodothiophene, 2-bromobenzonitrile, 1-bromo-4-methylbenzene, 1-bromo-4-methoxybenzene, 1-bromo-4-trifluoromethylbenzene, methyl-4-bromobenzoic acid, 1-bromo-4-nitrobenzene, 2-bromopyridine, and 2-bromothiophene.

[0028] In one embodiment of the present application, in (b), the supply flow rate of the compound represented by Chemical Formula 2 is about 7 mL / min to about 9 mL / min, and the R 1 The supply flow rate of the ZnCl 2The supply flow rate of the compound represented by Chemical Formula 2 may be about 7 mL / min to about 9 mL / min, about 7 mL / min to about 8.5 mL / min, about 7.5 mL / min to about 9 mL / min, or about 7.5 mL / min to about 8.5 mL / min. 1 The supply flow rate of the ZnCl may be about 1 mL / min to about 3 mL / min, about 1 mL / min to about 2.5 mL / min, about 1.5 mL / min to about 3 mL / min, or about 1.5 mL / min to about 2.5 mL / min. 2 The supply flow rate of the compound represented by Chemical Formula 2 in (b) may be about 8 mL / min to about 1.5 mL / min. 1 The flow rate of the ZnCl 2 Most preferably, the feed flow rate is about 1 mL / min.

[0029] In one embodiment of the present application, the first microtube reactor may have a length of about 30 cm to about 70 cm and an inner diameter of about 0.5 mm to about 2 mm. In one embodiment of the present application, the first microtube reactor may have a length of about 30 cm to about 70 cm, about 30 cm to about 60 cm, about 40 cm to about 70 cm, or about 40 cm to about 60 cm, and an inner diameter of about 0.5 mm to about 2 mm, or about 0.5 mm to about 1.5 mm. In one embodiment of the present application, the first microtube reactor most preferably has a length of about 50 cm and an inner diameter of about 1 mm.

[0030] In one embodiment of the present application, the length of the second microtube reactor may be about 150 cm to about 250 cm, and the inner diameter may be about 0.5 mm to about 2 mm. In one embodiment of the present application, the length of the second microtube reactor may be about 150 cm to about 250 cm, about 150 cm to about 240 cm, about 150 cm to about 230 cm, about 150 cm to about 220 cm, about 150 cm to about 210 cm, about 160 cm to about 250 cm, about 160 cm to about 240 cm, about 160 cm to about 230 cm, about 160 cm to about 220 cm, about 160 cm to about 210 cm, about 170 cm to about 250 cm, about 170 cm to about 240 cm, about 170 cm to about 230 cm, about 170 cm to about The length of the second microtube reactor may be about 220 cm, about 170 cm to about 210 cm, about 180 cm to about 250 cm, about 180 cm to about 240 cm, about 180 cm to about 230 cm, about 180 cm to about 220 cm, about 180 cm to about 210 cm, about 190 cm to about 250 cm, about 190 cm to about 240 cm, about 190 cm to about 230 cm, about 190 cm to about 220 cm, or about 190 cm to about 210 cm, and the inner diameter of the second microtube reactor may be about 0.5 mm to about 2 mm or about 0.5 mm to about 1.5 mm. In one embodiment of the present application, the length of the second microtube reactor is most preferably about 200 cm, and the inner diameter is most preferably about 1 mm.

[0031] In one embodiment of the present application, the reaction temperature in the first microtube reactor and the second microtube reactor may be independently about -50°C to about -30°C. In one embodiment of the present application, the reaction temperature in the first microtube reactor and the second microtube reactor may be independently about -50°C to about -30°C, about -50°C to about -35°C, about -45°C to about -30°C, or about -45°C to about -35°C. In one embodiment of the present application, the reaction temperature in the first microtube reactor and the second microtube reactor is most preferably about -40°C.

[0032] In one embodiment of the present application, in (b), the compound represented by Formula 2 is protected with a tosyl group to improve selectivity, and R 1 -Li to obtain the first intermediate product in which Li is coupled to the third carbon of the compound represented by Formula 2. In one embodiment of the present application, the first intermediate product and ZnCl are reacted in the second microtube reactor. 2 may react with Li to exchange for Zn, thereby obtaining the second intermediate product.

[0033] In one embodiment of the present application, the second intermediate product and R 2 -X 2 may be subjected to a Negishi reaction in the presence of a palladium (Pd)-containing catalyst at room temperature for about 4 hours to obtain the compound represented by Formula 3. In an embodiment of the present application, the yield of the compound represented by Formula 3 may be about 60% or more, or about 65% or more.

[0034] In an embodiment of the present application, (c) may be a reaction of the compound represented by Formula 3 with a pyridine compound in the presence of a Pd-containing catalyst and an organic solvent. In an embodiment of the present application, the pyridine compound may be, but is not limited to, 2-(tributylstannyl)pyridine.

[0035] In one embodiment of the present application, for example, in (c), about 1 equivalent of the compound represented by Formula 3, about 2 equivalents of 2-(tributylstannyl)pyridine, about 1 equivalent of Pd(PPh 3 ) 4 The compound represented by Formula 4 may be obtained by still further reacting about 10 mol % of the toluene with about 0.15 M at about 100° C. for about 12 hours.

[0036] In an embodiment of the present application, the yield of the compound represented by Formula 4 may be about 80% or more, or about 85% or more.

[0037] In one embodiment of the present application, the Negishi reaction and the Stille reaction may each be carried out in the presence of a Pd-containing catalyst.

[0038] In one embodiment of the present application, the Pd-containing catalyst is tetrakis(triphenylphosphine)palladium (Pd(PPh 3 ) 4 ), palladium acetate (Pd(OAc) 2 ), (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (XPhos Pd G3), and 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos), but are not limited thereto.

[0039] In an embodiment of the present disclosure, the Stille reaction may involve coupling a pyridine compound to the fifth carbon of the compound represented by Formula 3.

[0040] In one embodiment of the present application, for example, in (d), about 1 equivalent of the compound represented by Chemical Formula 4 may be dissolved in about 0.1 M of a solvent (THF / MeOH) in which tetrahydrofuran (THF) and methanol are mixed in a ratio of 1:1, and about 2 equivalents of about 1N sodium hydroxide may be added to the mixture while stirring at room temperature, and reacted for about 1 hour to remove the tosyl group. In one embodiment of the present application, the mixture may be added with about 0.1 M of dichloromethane solvent, about 1.3 equivalents of phenylboronic acid, and copper acetate (Cu(OAc) 2 The perampanel derivative represented by Chemical Formula 5 may be obtained by adding about 5 mol % of ethyl acetate and about 2 equivalents of pyridine, and stirring at room temperature for about 3 hours to carry out the Chan-Lam reaction.

[0041] In one embodiment of the present application, the Chan-Lam reaction is carried out by reacting phenylboronic acid and copper acetate (Cu(OAc) 2 ) may be carried out in the presence of a catalyst.

[0042] In some embodiments, the yield of the perampanel derivative may be about 70% or more. In some embodiments, the yield of the perampanel derivative may be about 70% or more, about 80% or more, or about 90% or more.

[0043] A second aspect of the present application provides a perampanel derivative produced by the method according to the first aspect.

[0044] Detailed descriptions of parts that overlap with the first aspect of the present application are omitted, but the contents described with respect to the first aspect of the present application may be similarly applied even if the description is omitted in the second aspect of the present application.

[0045] A third aspect of the present application is a compound represented by the following formula 2 and R 1 (II) supplying ZnCl2 to a first microtube reactor and reacting the ZnCl2 to obtain a first intermediate product; and (II) reacting the ZnCl2 with the first intermediate product. 2into a second microtube reactor and react to obtain a second intermediate product; and (III) reacting the second intermediate product and R 2 -X 2 by Negishi reaction to obtain a compound represented by the following chemical formula 3: [ka] [ka] In the above Chemical Formula 2 and Chemical Formula 3, R 1 -Li, and R 2 -X 2 In R 1 is a linear or branched C 1-8 is an alkyl group, R 2 teeth, [ka] and R 2 The wavy line in the substituent represented by the formula: represents a linking site, X 1 and X 2 are each independently Br or I.

[0046] Detailed descriptions of parts that overlap with the first and second aspects of the present application are omitted, but the contents described for the first and second aspects of the present application may be similarly applied even if the description is omitted in the third aspect of the present application.

[0047] In one embodiment of the present application, in (I), the supply flow rate of the compound represented by Chemical Formula 2 is about 7 mL / min to about 9 mL / min, and the R 1 The supply flow rate of the ZnCl 2In one embodiment of the present application, the supply flow rate of the compound represented by Chemical Formula 2 in (I) may be about 7 mL / min to about 9 mL / min, about 7 mL / min to about 8.5 mL / min, about 7.5 mL / min to about 9 mL / min, or about 7.5 mL / min to about 8.5 mL / min, and the supply flow rate of the compound represented by Chemical Formula 2 in (I) may be about 7 mL / min to about 9 mL / min, about 7 mL / min to about 8.5 mL / min, or about 7.5 mL / min to about 8.5 mL / min. 1 The supply flow rate of -Li may be about 1 mL / min to about 3 mL / min, about 1 mL / min to about 2.5 mL / min, about 1.5 mL / min to about 3 mL / min, or about 1.5 mL / min to about 2.5 mL / min. 2 The supply flow rate of the compound represented by the formula 2 in (I) may be about 8 mL / min to about 1.5 mL / min. 1 The supply flow rate of the ZnCl 2 Most preferably, the feed flow rate is about 1 mL / min.

[0048] In one embodiment of the present application, the first microtube reactor may have a length of about 30 cm to about 70 cm and an inner diameter of about 0.5 mm to about 2 mm. In one embodiment of the present application, the first microtube reactor may have a length of about 30 cm to about 70 cm, about 30 cm to about 60 cm, about 40 cm to about 70 cm, or about 40 cm to about 60 cm, and an inner diameter of about 0.5 mm to about 2 mm, or about 0.5 mm to about 1.5 mm. In one embodiment of the present application, the first microtube reactor most preferably has a length of about 50 cm and an inner diameter of about 1 mm.

[0049] In one embodiment of the present application, the length of the second microtube reactor may be about 150 cm to about 250 cm, and the inner diameter may be about 0.5 mm to about 2 mm. In one embodiment of the present application, the length of the second microtube reactor may be about 150 cm to about 250 cm, about 150 cm to about 240 cm, about 150 cm to about 230 cm, about 150 cm to about 220 cm, about 150 cm to about 210 cm, about 160 cm to about 250 cm, about 160 cm to about 240 cm, about 160 cm to about 230 cm, about 160 cm to about 220 cm, about 160 cm to about 210 cm, about 170 cm to about 250 cm, about 170 cm to about 240 cm, about 170 cm to about 230 cm, about 170 cm to about The length of the second microtube reactor may be about 220 cm, about 170 cm to about 210 cm, about 180 cm to about 250 cm, about 180 cm to about 240 cm, about 180 cm to about 230 cm, about 180 cm to about 220 cm, about 180 cm to about 210 cm, about 190 cm to about 250 cm, about 190 cm to about 240 cm, about 190 cm to about 230 cm, about 190 cm to about 220 cm, or about 190 cm to about 210 cm, and the inner diameter of the second microtube reactor may be about 0.5 mm to about 2 mm or about 0.5 mm to about 1.5 mm. In one embodiment of the present application, the length of the second microtube reactor is most preferably about 200 cm, and the inner diameter is most preferably about 1 mm.

[0050] In one embodiment of the present application, the reaction temperature in the first microtube reactor and the second microtube reactor may be independently about −50° C. to about −30° C. In one embodiment of the present application, the reaction temperature in the first microtube reactor and the second microtube reactor may be independently about −50° C. to about −30° C., about −50° C. to about −35° C., about −45° C. to about −30° C., or about −45° C. to about −35° C. EXAMPLES

[0051] Hereinafter, the present application will be described in more detail with reference to examples. However, the following examples are merely illustrative to aid in understanding the present application, and the contents of the present application are not limited to the following examples.

[0052] [Example] 1. Perampanel synthesis scheme (Figure 1) Perampanel was synthesized in four steps. A tosyl (Ts) group was introduced into the pyridine starting material (compound a below) to produce a protected pyridine (compound b below). Compound b was then selectively lithiated and zincated using a continuous flow process system, and this was then subjected to the Negishi reaction to obtain compound c below. Compound c was then subjected to a Stille reaction to couple to the 5th carbon to obtain compound d below. Finally, compound d was subjected to a tosyl group removal reaction and a Chan-Lam coupling reaction to obtain the final product, perampanel (compound e below).

[0053] [ka] [ka] [ka] [ka] [ka]

[0054] 2. Perampanel synthesis method 1) Synthesis of compound b (Figure 2) 1 equivalent of the compound a (3,5-dibromopyridin-2-ol), 1.2 equivalents of tosyl chloride (TsCl) and 5 mol% of 4-dimethylaminopyridine (DMAP) were placed in a round-bottom flask, and 0.23 M of dichloromethane (DCM) solvent was added. While stirring the mixture at 0° C., triethylamine (Et 3 N) 2 equivalents were slowly added dropwise to the mixture. After the reaction was carried out at 0°C for 12 hours, only the organic solvent layer was extracted with distilled water, and the water was removed with magnesium sulfate, and the solvent was removed under low pressure. Then, the compound b was obtained in 96% yield by performing column chromatography.

[0055] 2) Synthesis of compound c (continuous flow process) (Figure 3) Two T-shaped micromixers (M1 and M2); two microtube reactors (R T 1 and R T 2 ); and three tubes (P, P1, and P2) (P, P1, and P2 have an inner diameter (Ψ) = 1000 μm and a length (L) = 50 cm, respectively) were assembled as shown in Figure 3 to complete the continuous flow process system. The compound b (0.2 M in 2-methyltetrahydrofuran) (flow rate: 8.0 mL / min) and n-butyl lithium (n-BuLi) (0.808 M in hexane) (flow rate: 2.0 mL / min) were introduced into M1 (Ψ = 250 μm) using a syringe pump, and R T 1 (Ψ=1000μm, L=50cm). Then, R T 1 The mixture that passed through the pores was dissolved in zinc chloride (ZnCl 2 ) (1.28 M in 2-methyltetrahydrofuran) (flow rate: 1.0 mL / min) solution, and then R T 2 (Ψ=1000μm, L=200cm). RT 2 The mixture that had reached normal temperature was mixed with 1 equivalent of 2-iodobenzonitrile and tetrakis(triphenylphosphine)palladium(0) (Pd(PPh 3 ) 4 The reaction was carried out by stirring at room temperature for 4 hours. After the reaction was completed, the solvent was removed at low pressure and column chromatography was performed to obtain the compound c in a yield of 68%. The yield was calculated based on the reaction amount of 2-iodobenzonitrile.

[0056] 2-1) Synthesis of derivatives of compound c 1 R T 2 The mixture that had reached a normal state in step 2 was stirred with 1-iodo-4-methylbenzene or 1-bromo-4-methylbenzene for 3 hours, and the same continuous flow process was carried out as in step 2 above, to obtain a derivative of compound c in a yield of 81%. The yield was calculated based on the reaction amount of 1-iodo-4-methylbenzene or 1-bromo-4-methylbenzene, and the yield of the derivative obtained was 81%. 1 The H-NMR spectrum is shown in FIG.

[0057] 2-2) Synthesis of derivatives of compound c 2 R T 2 The mixture that had reached a normal state in step 2 was stirred with 1-iodo-4-methoxybenzene or 1-bromo-4-methoxybenzene for 3 hours, and the same continuous flow process was carried out as in step 2 above, to obtain a derivative of compound c in a 92% yield. The yield was calculated based on the reaction amount of 1-iodo-4-methoxybenzene or 1-bromo-4-methoxybenzene, and the yield of the derivative obtained was 92%. 1 The H-NMR spectrum is shown in FIG.

[0058] 2-3) Synthesis of derivatives of compound c3 R T 2The mixture that had reached a normal state in step 2 was stirred with 1-iodo-4-trifluoromethylbenzene or 1-bromo-4-trifluoromethylbenzene for 4 hours, and the same continuous flow process was carried out as in step 2) above, to obtain a derivative of compound c with a yield of 75%. The yield was calculated based on the reaction amount of 1-iodo-4-trifluoromethylbenzene or 1-bromo-4-trifluoromethylbenzene, and the yield of the derivative obtained was 75%. 1 The H-NMR spectrum is shown in FIG.

[0059] 2-4) Synthesis of derivatives of compound c4 R T 2 The mixture that had reached a normal state in step 2 was stirred with methyl 4-iodobenzoate or methyl 4-bromobenzoate for 3 hours, and the same continuous flow process was carried out as in step 2 above, to obtain a derivative of compound c in a yield of 91%. The yield was calculated based on the reaction amount of methyl 4-iodobenzoate or methyl 4-bromobenzoate, and the yield of the derivative obtained was 91%. 1 The H-NMR spectrum is shown in FIG.

[0060] 2-5) Synthesis of derivatives of compound c5 R T 2 The mixture that had reached a normal state in step 2 was stirred with 1-iodo-4-nitrobenzene or 1-bromo-4-nitrobenzene for 3 hours, and the same continuous flow process was carried out as in step 2 above, to obtain a derivative of compound c in a yield of 81%. The yield was calculated based on the reaction amount of 1-iodo-4-nitrobenzene or 1-bromo-4-nitrobenzene, and the yield of the derivative obtained was 81%. 1 The H-NMR spectrum is shown in FIG.

[0061] 2-6) Synthesis of derivatives of compound c6 R T 2The mixture that had reached a normal state in step 2 was stirred with 2-iodopyridine or 2-bromopyridine for 5 hours, and the same continuous flow process was carried out as in step 2) above, to obtain a derivative of compound c with a yield of 95%. The yield was calculated based on the reaction amount of 2-iodopyridine or 2-bromopyridine, and the yield of the derivative obtained was 95%. 1 The H-NMR spectrum is shown in FIG.

[0062] 2-7) Synthesis of derivatives of compound c7 R T 2 The mixture that had reached a normal state in step 2 was stirred with 2-iodothiophene or 2-bromothiophene for 5 hours, and the same continuous flow process was carried out as in step 2) above, to obtain a compound c derivative with a yield of 91%. The yield was calculated based on the amount of 2-iodothiophene or 2-bromothiophene reacted, and the yield of the obtained derivative was 91%. 1 The H-NMR spectrum is shown in FIG.

[0063] 3) Synthesis of compound d (Figure 11) The compound c was added in an amount of 1 equivalent, and 2-(tributylstannyl)pyridine was added in an amount of 2 equivalents. 3 ) 4 10 mol% was placed in a round-bottom flask, and 0.15 M toluene solvent was added. The mixture was stirred at 100°C and the reaction was allowed to proceed for 12 hours. The reaction product was filtered through celite, and the solvent was removed under low pressure. Compound d was then obtained in 87% yield by column chromatography.

[0064] 4) Synthesis of perampanel (Figure 12) In a round-bottom flask, 1 equivalent of compound d was dissolved in a 0.1M solvent (THF / MeOH) in which tetrahydrofuran (THF) and methanol were mixed in a 1:1 ratio. While stirring the mixture at room temperature, 2 equivalents of 1N sodium hydroxide (NaOH) were added to the mixture and reacted for 1 hour. After neutralizing with pH paper by acid-base extraction, only the organic solvent layer was extracted, water was removed with magnesium sulfate, and the solvent was removed under low pressure. Then, 0.1M dichloromethane solvent, 1.3 equivalents of phenylboronic acid, and copper acetate (Cu(OAc)) were added to the mixture. 2 5 mol% of sodium bicarbonate (NaHCO 3 ) and 2 equivalents of pyridine were added, and the mixture was stirred at room temperature for 3 hours to allow the reaction to proceed. 3 The organic solvent layer was extracted using ethylenediaminetetraacetic acid (EDTA) and magnesium sulfate to remove water, and the solvent was removed at low pressure. After that, column chromatography was performed to obtain the final product, perampanel, in a 70% yield.

[0065] The above description of the present application is for illustrative purposes only, and a person having ordinary skill in the art to which the present application pertains should understand that the present application can be easily modified into other specific forms without changing the technical idea or essential features of the present application. Therefore, it should be understood that the above-described embodiments are illustrative in all respects and are not limiting. For example, each component described as a single type may be implemented in a distributed form, and similarly, each component described as a distributed type may be implemented in a combined form.

[0066] The scope of the present application is indicated by the claims set forth below rather than by the above detailed description, and all modifications and variations derived from the meaning and scope of the claims, as well as their equivalent concepts, should be construed as being included within the scope of the present application.

Claims

1. (a) protecting a compound represented by the following formula 1 with a tosyl group to obtain a compound represented by the following formula 2: (b) a compound represented by the following chemical formula 2 and R １ -Li is supplied to a first microtube reactor and reacted to obtain a first intermediate product; The first intermediate product and ZnCl ２ into a second microtube reactor and react to obtain a second intermediate product; The second intermediate product and R ２ -X ２ by subjecting the compound to a Negishi reaction to obtain a compound represented by the following chemical formula 3: (c) obtaining a compound represented by the following formula 4 by subjecting a compound represented by the following formula 3 to a Stille reaction with 2-(tributylstannyl)pyridine; and (d) subjecting a compound represented by the following formula 4 to a tosylation reaction and a Chan-Lam reaction to obtain a perampanel derivative represented by the following formula 5: The method for producing a perampanel derivative comprises: 【Chemistry 1】 【Chemistry 2】 【Chemistry 3】 【Chemistry 4】 【Chemistry 5】 The Chemical Formulas 1 to 5, R １ -Li, and the R ２ -X ２ In The R １ is a linear or branched C １－８ is an alkyl group, The R ２ teeth, 【Chemistry 6】 and The R ２ The wavy line in the substituent represented by the formula: represents a linking site, The X １ and the X ２ are each independently Br or I.

2. In the above (b), The flow rate of the compound represented by the formula 2 is 7 mL / min to 9 mL / min. １ The supply flow rate of the ZnCl ２ The method for producing a perampanel derivative according to claim 1, wherein the supply flow rate is 0.5 mL / min to 1.5 mL / min.

3. 2. The method for producing a perampanel derivative according to claim 1, wherein the first microtube reactor has a length of 30 cm to 70 cm and an inner diameter of 0.5 mm to 2 mm.

4. 2. The method for producing a perampanel derivative according to claim 1, wherein the second microtube reactor has a length of 150 cm to 250 cm and an inner diameter of 0.5 mm to 2 mm.

5. 2. The method for producing a perampanel derivative according to claim 1, wherein the reaction temperatures in the first microtube reactor and the second microtube reactor are each independently −50° C. to −30° C.

6. The method for producing a perampanel derivative according to claim 1 , wherein the Negishi reaction and the Stille reaction are each carried out in the presence of a Pd-containing catalyst.

7. The method for producing a perampanel derivative according to claim 1 , wherein the Stille reaction is a coupling reaction of a pyridine compound to the fifth carbon of the compound represented by Chemical Formula 3.

8. The Chan-Lam reaction is carried out by reacting phenylboronic acid with copper acetate (Cu(OAc) ２ The method for producing the perampanel derivative according to claim 1 , wherein the method is carried out in the presence of a catalyst.

9. 2. The method for producing a perampanel derivative according to claim 1, wherein the yield of the perampanel derivative is 70% or more.

10. A perampanel derivative produced by the method according to claim 1.

11. (I) A compound represented by the following chemical formula 2 and R １ -Li is supplied to a first microtube reactor and reacted to obtain a first intermediate product; and (II) the first intermediate product and ZnCl ２ into a second microtube reactor and react therein to obtain a second intermediate product. A continuous flow process comprising: (III) the second intermediate product and R ２ -X ２ By subjecting the compound to the Negishi reaction, a compound represented by the following chemical formula 3 is obtained. A method for arylation of a pyridine compound, comprising: 【Chemistry 7】 【Chemistry 8】 The Chemical Formula 2, the Chemical Formula 3, and the R １ -Li, and the R ２ -X ２ In The R １ is a linear or branched C １－８ is an alkyl group, The R ２ teeth, 【Chemistry 9】 and The R ２ The wavy line in the substituent represented by the formula: represents a linking site, The X １ and the X ２ are each independently Br or I.

12. In the above (I), the supply flow rate of the compound represented by the chemical formula 2 is 7 mL / min to 9 mL / min, １ -Li supply flow rate is 1 mL / min to 3 mL / min; In the above (II), the ZnCl ２ The method for arylation of pyridine compounds according to claim 11, wherein the feed flow rate of is 0.5 mL / min to 1.5 mL / min.

13. 12. The method for arylation of pyridine compounds according to claim 11, wherein the length of the first microtube reactor is 30 cm to 70 cm, and the inner diameter is 0.5 mm to 2 mm.

14. 12. The method for arylation of pyridine compounds according to claim 11, wherein the length of the second microtube reactor is 150 cm to 250 cm, and the inner diameter is 0.5 mm to 2 mm.

15. 12. The method for arylation of a pyridine compound according to claim 11, wherein the reaction temperatures in the first microtube reactor and the second microtube reactor are each independently −50° C. to −30° C.

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